Scientists have solved a biological mystery that remained unanswered for more than three decades, uncovering an unexpected way the immune system protects the body from its own inflammatory response. The breakthrough reveals that a chemical signal responsible for attracting immune cells to fight infections also helps prevent those same defenses from damaging healthy tissue.
The discovery came from researchers at Memorial Sloan Kettering Cancer Center (MSK), who took an unusual approach to studying inflammation. Rather than relying on mice, a standard choice for biomedical research, they turned to zebrafish. That decision helped them identify a long-mysterious enzyme and uncover a protective mechanism that had previously escaped scientists.
The findings, published October 7 in Nature, could advance research into cancer, inflammatory bowel disease, and asthma. They also raise the possibility of developing treatments that strengthen the body’s natural defenses against inflammatory damage.
A Scientific Mystery Dating Back to 1992
The mystery began in 1992, when researchers at McGill University investigated a molecule that helps direct immune cells toward sites of infection. Known as 5-oxoETE, or 5-oxo-6,8,11,14-eicosatetraenoic acid, this fatty signaling molecule acts as a chemical alert when the body needs to respond to a threat.
At the time, scientists observed an enzyme that could both produce and break down 5-oxoETE. Enzymes are proteins that help chemical reactions take place, but in this case, researchers could not identify the human gene responsible for making the enzyme.
That missing genetic information created a major obstacle. Without knowing which gene produced the enzyme, scientists could not easily manipulate it in experiments or determine how problems with its activity might contribute to disease. Researchers assigned the enzyme a descriptive name based on its chemical function, but its genetic identity remained unknown for more than 30 years.
The breakthrough finally came through the work of Yanan Ma, PhD, a postdoctoral researcher at MSK’s Sloan Kettering Institute. Building on earlier investigations by former lab colleague King Lam Hui, PhD, Ma identified the human gene that produces the enzyme, giving researchers a way to examine its function much more closely.
How the Immune System Can Damage Healthy Cells
Ma works in the laboratory of cell biologist Philipp Niethammer, PhD, whose research examines how cells respond to injuries, infections, and other forms of stress. His team focuses on inflammation, tissue repair, and regeneration, biological processes that also play important roles in cancer and numerous other diseases.
When harmful bacteria enter the body, chemical signals help recruit specialized white blood cells to the affected area. One of those signals is 5-oxoETE, which attracts immune cells equipped to attack invading microorganisms.
Although this response is essential for fighting infections, it carries risks. The substances immune cells release to destroy pathogens can also injure surrounding healthy tissue.
“They flood the site with toxic substances to kill the bacteria,” Dr. Niethammer says. “But this can cause damage to healthy cells if it gets out of control.”
Niethammer’s laboratory had already spent years investigating the molecular reactions involved in 5-oxoETE signaling. Researchers were gradually identifying how the different components of the system worked together, but the unknown enzyme remained a major missing piece.
Why Zebrafish Succeeded Where Mice Could Not
Most biomedical experiments involving animals use mice or rats because their biological systems share many similarities with humans. However, these familiar laboratory animals had a significant limitation for the question Ma and her colleagues wanted to answer.
“Mice and rats are the primary model used in biomedical research,” says Dr. Ma, who received a prestigious Marie-Josée Kravis WISE Fellowship in 2023 for her work on the pathway. “It makes sense — they’re mammals, and there’s about an 80% overlap between their genes and ours.”
Despite those similarities, mice lack a known immune cell receptor capable of recognizing 5-oxoETE. Without that receptor, researchers cannot investigate the complete signaling process in mice.
Zebrafish, however, have retained the necessary biological machinery.
“This means that you can’t study the pathway in mice,” Dr. Ma says. “But the pathway is intact in fish. So picking the right alternative model was critical to advancing our understanding of how the human body responds.”
Using zebrafish allowed the scientists to explore how the signal operates in a living organism and eventually helped reveal a function that had gone unnoticed for decades.
Scientists Finally Identify the Missing Enzyme
Before investigating the process in zebrafish, Ma and Hui began searching for the enzyme’s genetic origins using cultured human cells.
They selected several genes that might be responsible and systematically switched them off, looking for changes in the enzyme’s activity. One candidate produced a decisive result.
When Ma disabled a gene called DHRS7, the enzyme stopped functioning. The experiment established that DHRS7 was the gene researchers had been searching for since the early 1990s.
Additional tests involving the rodent version of the gene showed almost no enzyme activity. That result was consistent with the absence of the 5-oxoETE receptor in mice, suggesting that rodents had lost key functions associated with this signaling system.
Identifying DHRS7 resolved the long-standing mystery. It also connected Ma’s research with a separate investigation underway in the same laboratory, led by postdoctoral researcher Miklos Lengyel, MD, PhD.
“Typically, when you have a paper with two first authors like Yanan and Miklos, there is just one story that two people contributed to equally,” Dr. Niethammer says. “But this paper is not like that. In this paper, there are two separate projects led by two different authors that came together as one larger discovery. And I think that’s extremely important to note.”
A Surprising Result Turns Expectations Upside Down
While Ma investigated the mysterious enzyme, Lengyel was using zebrafish to study colitis, an inflammatory condition affecting the colon. His experiments involved disabling selected genes to understand how they influenced intestinal inflammation.
One experiment produced an especially puzzling outcome.
Lengyel removed a gene called hcar1-4 (the zebrafish version of the human gene OXER1). This gene produces the receptor that recognizes 5-oxoETE and allows cells to respond to its signal.
Because 5-oxoETE helps attract immune cells and initiate inflammation, removing its receptor should theoretically weaken that response.
“So if you remove the receptor that detects the signal, you’d expect less inflammation, not more,” Dr. Lengyel says.
Instead, the zebrafish developed intestinal inflammation on their own, even though no infection was present.
The researchers initially considered whether neutrophils, the white blood cells normally recruited by the signal, might be responsible. However, removing those immune cells did not eliminate the inflammation.
This unexpected behavior suggested that the 5-oxoETE pathway was doing something much more complicated than simply activating the immune system.
Disabling an Inflammatory Signal Makes Inflammation Worse
The connection between the two research projects became clear after Ma identified DHRS7 as the gene responsible for producing the enzyme involved in 5-oxoETE signaling.
Lengyel then disabled DHRS7 in zebrafish, preventing the production of the enzyme and disrupting the signaling process.
Based on the molecule’s established role in attracting immune cells, the researchers expected inflammation to decrease. Instead, they observed the same surprising pattern seen when the receptor was removed: inflammation increased.
“It made absolutely no sense,” Dr. Lengyel says. “I had to prove using several different methods before the rest of the lab was convinced.”
The findings pointed to a previously unrecognized function. The signaling pathway did not simply help initiate the immune response. It also appeared to prevent unnecessary damage to healthy cells.
That dual responsibility explained why eliminating the pathway had such an unexpected effect. By disabling the system, scientists had removed not only an inflammatory signal but also an important source of cellular protection.
The Immune System’s Hidden Protective Shield
Further experiments revealed how this protection works.
When immune cells attack dangerous microorganisms, they release highly reactive substances that can harm nearby healthy cells. The 5-oxoETE pathway helps tissues withstand this chemical stress, reducing the risk that the body’s own defenses will cause unnecessary injury.
“This makes sense when you think about it,” Dr. Niethammer says. “These immune cells unleash chemical warfare against a pathogen, and organisms have evolved an elegant way of protecting healthy cells at the same time.”
The researchers found that zebrafish intestinal cells became particularly vulnerable when either 5-oxoETE or its Hcar1-4 receptor was missing. Even the normal bacteria living in the intestine produced enough low-level chemical stress to cause problems when this protective system was disabled.
The team traced the cellular protection to a group of enzymes known as NUDIX hydrolases. These enzymes help maintain cellular health by removing damaged DNA building blocks before they can interfere with normal biological processes.
Without the protective signaling pathway, intestinal cells could no longer withstand the chemical stress associated with ordinary gut bacteria. Some cells died, setting off an inflammatory response despite the absence of an invading pathogen.
The results revealed that the body uses the same molecular system both to call immune cells into action and to protect healthy tissue from the consequences.
“As it turns out, this signal isn’t just an alarm, it’s also a shield,” Dr. Niethammer says.
Potential Implications for Cancer and Inflammatory Diseases
Understanding this protective mechanism could have important implications for diseases involving excessive or poorly controlled inflammation.
The 5-oxoETE signaling pathway is known to be disrupted in conditions such as cancer, inflammatory bowel disease (IBD), and asthma. By identifying its previously unknown protective role, researchers have gained a new perspective on how those disruptions might contribute to tissue damage.
In human cancers, mutations affecting DHRS7 and OXER1 (the human version of hcar1-4) have been identified in tumors of the gastrointestinal tract and uterus.
Research has also linked mutations that prevent OXER1 from functioning properly with poorer outcomes in patients with colorectal, pancreatic, and kidney cancers.
The findings suggest that strengthening the pathway might eventually help healthy tissues tolerate damaging conditions more effectively. One possible application involves protecting the intestine from oxidative stress associated with cancer treatment.
“More research is needed, but there’s a possibility that activating the pathway could increase the resilience of the gut to oxidative stress — which might help counteract damage caused by radiation therapy or chemotherapy,” Dr. Lengyel says.
The discovery also has implications for diseases affecting mucosal tissues, the protective linings found in areas such as the intestines and respiratory tract.
In people with IBD, researchers have previously associated lower concentrations of 5-oxoETE in intestinal tissue with worse disease outcomes.
Evidence from asthma research points to another possible protective function. An independent study involving primates found that blocking OXER1 weakened the immune cell response but also caused protective mucus-producing cells in the airways to disappear.
Together, these observations suggest that attempts to suppress inflammation must account for the protective roles certain inflammatory signals perform. However, further research will be necessary to determine whether targeting this pathway can produce safe and effective treatments in humans.
How Physical Injury Activates the Same Defense System
The researchers are also investigating how this signaling pathway responds to physical damage, not just infection or chemical stress.
That aspect of the work is being explored by doctoral student Zaza Gelashvili, MS, who studies how cells detect mechanical forces associated with tissue injury.
When cells experience physical stress, changes to their membranes can initiate the same chain of molecular reactions involved in inflammation.
One early step occurs when stressed cell membranes release arachidonic acid, a fatty molecule that serves as the starting material for producing 5-oxoETE.
Gelashvili, a co-author of the Nature study, led a separate investigation into the molecular signals associated with physical wounds. That research was published in Nature Communications earlier in 2026. His contributions were also recognized with the 2026 Chairman’s Prize from the Gerstner Sloan Kettering Graduate School of Biomedical Sciences.
“There’s a mechanical component to the pathway that’s upstream of what Yanan and Miklos have been studying,” explains Gelashvili, a co-author on the study who led a separate study on physical wound signals that was published in Nature Communications earlier this year; his work was also recognized with the 2026 Chairman’s Prize from the Gerstner Sloan Kettering Graduate School of Biomedical Sciences. “You can think of it as the first step in a chain reaction: Physical stress unlocks the raw material, oxidative stress drives the conversion, and DHRS7 amplifies the signal.”
The research suggests that the body combines information about different forms of cellular stress to coordinate its response. Physical damage can initiate the process, chemical stress can influence the conversion of signaling molecules, and DHRS7 helps strengthen the resulting signal.
Rather than operating as separate responses, these processes appear to work together to help the body recognize danger while limiting unnecessary harm to healthy cells.
“What we are really studying is a pathway that integrates two completely different kinds of stress — mechanical and metabolic — and converts them into a single, coordinated, protective response,” Dr. Niethammer says.
Study Authors and Funding
Additional researchers contributing to the study were Yohannes Ambaw, Leehyeon Kim, Ritchie Ly, Siyang Peng, Meysoon Quraishi, Tobias Walther, and Robert Farese Jr., all affiliated with MSK.
Financial support came from the National Institutes of Health (R35GM140883); an MSK Basic Research Innovation Award; a Starr Foundation Program for Discovery Science grant; a Tow Foundation fellowship; a Marie-Josée Kravis Women in Science Endeavor (WISE) fellowship; a Crohn’s Colitis Foundation Research Fellows Award (1268111); an Experimental Immuno-Oncology Scholars fellowship; and core facility services supported in part by MSK’s National Cancer Institute Cancer Center Support grant (P30CA008748).
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